635318-11-5

Basic information

• Product Name: LY-404039
• Synonyms: LY-404039;LY2140023;(1R,4S,5S,6S)-4-Amino-2-thiabicyclo[3.1.0]hexane-4,6-dicarboxylic acid 2,2-dioxide;4-Amino-2-thiabicyclo(3.1.0)hexane-4,6-dicarboxylic acid;LY404039 3.03G;LY2140023/LY404039;(1R,4S,5S)-4-aMino-2-thiabicyclo[3.1.0]hexane-4,6-dicarboxylic acid 2,2-dioxide;(1R,4S,5S,6S)-4-AMINO-2-THIABICYCLO 3.1.0 HEXANE-4,6-DICARBOXYLIC ACID 2,2-DIOXIDE (LY 404039)
• CAS NO: 635318-11-5
• Molecular Formula: C7H9NO6S
• Molecular Weight: 235.215
• Product Categories: Inhibitors
• Mol File: 635318-11-5.mol

Chemical Properties

• Melting Point: >250 °C(Solv: water (7732-18-5))
• Boiling Point: 600.3±55.0 °C(Predicted)
• Appearance: /
• Density: 1.888
• Solubility: insoluble in DMSO; insoluble in EtOH; insoluble in H2O
• PKA: 1.15±0.40(Predicted)
• CAS DataBase Reference: LY-404039(CAS DataBase Reference)
• NIST Chemistry Reference: LY-404039(635318-11-5)
• EPA Substance Registry System: LY-404039(635318-11-5)

Safety Data

• Hazardous Substances Data: 635318-11-5(Hazardous Substances Data)

Usage

Uses

Used in Pharmaceutical Industry:
LY-404039 is used as a drug for the treatment of schizophrenia, specifically targeting the mGlu2/3 receptor to potentially improve cognitive impairment associated with the disorder.

Biological Activity

ly404039 is a potent and highly selective agonist of recombinant human mglu2 and mglu3 receptors and rat neurons expressing native mglu2/3 receptor with ki values of 149, 92 and 88 nm, respectively [1].the inhibition of forskolin-stimulated camp formation has indicated that ly404039 was a nanomolar potent agonist of human mglu2 (ec50 = 23 nm) and mglu3 (ec50 = 48 nm) receptors. additionally, ly404039 could concentration-dependently decrease excitatory postsynaptic potentials (epsps) in rat striatal spiny neuron (ec50 = 141 nm). ly404039 has also been reported to suppress the frequency of 5-ht-induced postsynaptic currents (ec50 = 82.3 nm) in rat prefrontal cortical slices [1].

references

[1] rorick-kehn lm1, johnson bg, burkey jl, wright ra, calligaro do, marek gj, nisenbaum es, catlow jt, kingston ae, giera dd, herin mf, monn ja,mckinzie dl, schoepp dd. pharmacological and pharmacokinetic properties of a structurally novel, potent, and selective metabotropic glutamate 2/3 receptor agonist: in vitro characterization of agonist (-)-(1r,4s,5s,6s)-4-amino-2-sulfonylbicyclo[3.1.0]-hexane-4,6-dicarboxylic acid (ly404039). j pharmacol exp ther. 2007 apr;321(1):308-17. epub 2007 jan 4. j pharmacol exp ther. 2007 apr;321(1):308-17. epub 2007 jan 4.

Upstream product

• 191471-72-4 (+/-)-ethyl 4-oxo-2-thiabicyclo<3.1.0>hex-3-ene-6-carboxylate 
• 635318-10-4 (-)-(1'R,4S,5'S,6'S)-2,5-dioxospiro(imidazolidine-4,4'-[2]-thiabicyclo[3.1.0]hexane)-6'-carboxylic acid 2',2'-dioxide 
• 926291-18-1 dimethyl (-)-(1R,4S,5S,6S)-4-(N-tert-butyloxycarbonylamino)-2-thiabicyclo[3.1.0]hexane-4,6-dicarboxylate-2,2-dioxide 
• 926291-17-0 dimethyl (+)-(1R,2R,4S,5S,6S)-4-(N-tert-butyloxycarbonylamino)-2-thiabicyclo[3.1.0]hexane-4,6-dicarboxylate-2-oxide 
• 635317-62-3 (1R,4S,5S,6S)-4-amino-2,2-dioxo-2λ⁶-thia-bicyclo[3.1.0]hexane-4,6-dicarboxylic acid dimethyl ester 
• 926291-15-8 dimethyl (-)-(1R,4S,5S,6S)-4-(N-tert-butyloxycarbonylamino)-2-thiabicyclo[3.1.0]hexane-4,6-dicarboxylate 
• 191471-53-1 LY 389795 
• 926291-21-6 4-amino-2-thia-bicyclo[3.1.0]hexane-4,6-dicarboxylic acid dimethyl ester 

Relevant articles and documents

Synthesis and metabotropic glutamate receptor activity of S-oxidized variants of (-)-4-amino-2-thiabicyclo-[3.1.0]hexane-4,6-dicarboxylate: Identification of potent, selective, and orally bioavailable agonists for mGlu2/3 receptors

(-)-4-Amino-2-thiabicyclo-[3.1.0]hexane-4,6-dicarboxylate (LY389795, (-)-3) is a highly potent and selective agonist of metabotropic glutamate receptors 2 (mGlu2) and 3 (mGlu3). As part of our ongoing research program, we have prepared S-oxidized variants of (-)-3, compounds (-)-10, (+)-11 (LY404040), and (-)-12 (LY404039). Each of these chiral heterobicyclic amino acids displaced specific binding of the mGlu2/3 receptor antagonist 3H-2S-2-amino-2-(1S,25-2- carboxycycloprop-1-yl)-3-(xanth-9-yl)propanoic acid (3H-LY341495) from membranes expressing recombinant human mGlu2 or mGlu3 and acted as potent agonists in cells expressing these receptor subtypes. Docking of the most potent of these derivatives, (+)-11, to mGlu2 revealed the possibility of an additional H-bond interaction between the sulfoxide oxygen of (+)-11 with tyrosine residue Y236. Pharmacokinetic analysis of mGlu active enantiomers (+)-11 and (-)-12 in rats showed each to be well absorbed following oral administration. Consistent with their mGlu2/3 agonist potency and pharmacokinetic properties, both (+)-11 and (-)-12 blocked phencyclidine-evoked ambulations in a dose-dependent manner, indicating their potential as nonclassical antipsychotic agents.

Process development for a key synthetic intermediate of LY2140023, a clinical candidate for the treatment of schizophrenia

To fuel clinical development of the experimental CNS medicine LY2140023, we developed a scalable route for the multistep synthesis of a pivotal synthetic intermediate. The core of the conformationally restricted glutamic acid-based amino acid analogue was built via a Rh-catalyzed cyclopropanation of thiophene. Regioselective functionalization of the remaining double bond was achieved by a hydroboration/oxidation sequence followed by a Bucherer-Bergs reaction to give a hydantoin with the targeted l-glutamic acid configuration. Subsequent resolution, oxidation state, and protecting group manipulations gave the key intermediate in an overall nine-step scalable streamlined route starting from thiophene.

PRODRUGS OF EXCITATORY AMINO ACIDS

This invention relates to synthetic excitatory amino acid prodrugs and processes for their preparation. The invention further relates to methods of using, and pharmaceutical compositions comprising, the compounds for the treatment of neurological disorder